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Cited by 183Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeuroscience and Neuropharmacology Research

Apolipoprotein E4, inhibitory network dysfunction, and Alzheimer’s disease

Open access
Najm, Ramsey, Jones, Emily A., Huang, Yadong·2019·Molecular Neurodegeneration
DOI 10.1186/s13024-019-0324-6PMC PMC6558779
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Abstract

Apolipoprotein (apo) E4 is the major genetic risk factor for Alzheimer's disease (AD), increasing risk and decreasing age of disease onset. Many studies have demonstrated the detrimental effects of apoE4 in varying cellular contexts. However, the underlying mechanisms explaining how apoE4 leads to cognitive decline are not fully understood. Recently, the combination of human induced pluripotent stem cell (hiPSC) modeling of neurological diseases in vitro and electrophysiological studies in vivo have begun to unravel the intersection between apoE4, neuronal subtype dysfunction or loss, subsequent network deficits, and eventual cognitive decline. In this review, we provide an overview of the literature describing apoE4's detrimental effects in the central nervous system (CNS), specifically focusing on its contribution to neuronal subtype dysfunction or loss. We focus on γ-aminobutyric acid (GABA)-expressing interneurons in the hippocampus, which are selectively vulnerable to apoE4-mediated neurotoxicity. Additionally, we discuss the importance of the GABAergic inhibitory network to proper cognitive function and how dysfunction of this network manifests in AD. Finally, we examine how apoE4-mediated GABAergic interneuron loss can lead to inhibitory network deficits and how this deficit results in cognitive decline. We propose the following working model: Aging and/or stress induces neuronal expression of apoE. GABAergic interneurons are selectively vulnerable to intracellularly produced apoE4, through a tau dependent mechanism, which leads to their dysfunction and eventual death. In turn, GABAergic interneuron loss causes hyperexcitability and dysregulation of neural networks in the hippocampus and cortex. This dysfunction results in learning, memory, and other cognitive deficits that are the central features of AD.

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Written from the paper’s full text.

TL;DR

This review proposes that apolipoprotein E4 (apoE4) selectively injures hippocampal GABAergic interneurons through a tau-dependent mechanism, causing inhibitory network dysfunction, hyperexcitability, and cognitive decline in Alzheimer’s disease (AD). It synthesizes in vivo and in vitro evidence to argue that intraneuronal apoE4, rather than astrocytic apoE4, is central to this interneuron vulnerability.

Key findings

  • ApoE4 is the major genetic risk factor for late-onset AD, present in roughly 20–25% of the human population and accounting for 60–75% of AD cases in most clinical studies; it increases risk and decreases age of onset in a gene-dose-dependent manner.
  • GABAergic interneurons, especially hippocampal somatostatin-positive hilar interneurons, are selectively vulnerable to apoE4-mediated toxicity; apoE4-KI mice show age- and tau-dependent loss of these interneurons, and tau removal rescues interneuron loss and learning/memory deficits.
  • The cellular source of apoE matters: neuronal apoE4 is proteolytically cleaved into neurotoxic fragments, whereas astrocytic apoE4 does not show the same detrimental effects; deletion of apoE4 in GABAergic interneurons, but not astrocytes, protects aged mice from interneuron loss and cognitive deficits.
  • Proposed consequences include inhibitory network dysfunction, hyperexcitability, seizures, olfactory deficits, default-mode-network and hippocampal hyperactivity, and reduced sharp-wave ripple/slow gamma activity; 10–22% of AD patients exhibit seizures, and epilepsy patients with at least one APOE4 allele are six times more likely to show treatment resistance.

Methods

  • Narrative review synthesizing published in vivo, in vitro, human post-mortem, imaging, electrophysiological, and clinical literature on apoE4, GABAergic interneurons, and AD.
  • No primary data collection or systematic meta-analysis is reported; the paper integrates findings from animal models, human induced pluripotent stem cell (hiPSC)-derived neurons, and human studies.
  • The authors present a working model in which aging/stress induces neuronal apoE expression; apoE4’s domain interaction makes it more susceptible to cleavage, generating neurotoxic fragments that drive tau-dependent GABAergic interneuron dysfunction and death, leading to network hyperexcitability and cognitive decline.

Limitations

  • The paper states that the mechanisms explaining how apoE4 leads to cognitive decline are not fully understood, that the molecular/cellular basis of GABAergic interneuron selective vulnerability remains unclear, and that more research and new animal models are required.
  • The paper notes conflicting findings on apoE’s roles in Aβ seeding/aggregation and on apoE isoform effects in tau models, which it attributes to differences in model systems, cell-type specificity, tau expression levels, mutation toxicity, and age.
  • Evident from the text: this is a narrative review without a systematic search or meta-analysis, and many central claims rely on animal and hiPSC models; clinical therapeutic evidence is described as limited by small cohorts and short treatment periods.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1186/s13024-019-0324-6

Cites

212 of 212 references verified0 citation errors · 0 not checkable

Statistics

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Claims the paper makes

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  • Premisecitation

    Astrocytes are the primary source of apoE in the brain.

    “Astrocytes are the primary source of apoE in the brain [23, 24].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [23] Grehan S, Tse E, Taylor JM. Two distal downstream enhancers direct expression of the human apolipoprotein E gene to astrocytes in the brain. J Neurosci. 2001;21(3):812–22. source

      Not checked in the free run.

    • cites [24] Pitas RE, Boyles JK, Lee SH, Foss D, Mahley RW. Astrocytes synthesize apolipoprotein E and metabolize apolipoprotein E-containing lipoproteins. Biochim Biophys Acta (BBA)/Lipids Lipid Metab. 1987;917(1):148–61. source

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  • Premisecitation

    Cellular origin plays a crucial role in apoE's biophysical properties and pathological effects.

    “Cellular origin plays a crucial role in apoE’s biophysical properties and pathological effects.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [27] Shi Y, Holtzman DM. Interplay between innate immunity and Alzheimer disease: APOE and TREM2 in the spotlight. Nat Rev Immunol. 2018. https://doi.org/10.1038/s41577-018-0051-1 . source

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  • Premisecitation

    The apoE4 domain interaction renders apoE4 more susceptible to proteolytic cleavage, resulting in the generation of neurotoxic apoE4 fragments.

    “Importantly, this domain interaction renders apoE4 to be more susceptible to proteolytic cleavage, resulting in the generation of neurotoxic apoE4 fragments [20–22].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [20] Brecht WJ, Harris FM, Chang S, Tesseur I, Yu G-Q, Xu Q, et al. Neuron-specific apolipoprotein E4 proteolysis is associated with increased tau phosphorylation in brains of transgenic mice. J Neurosci. 2004;24(10):2527–34. source

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    • cites [21] Huang Y. Aβ-independent roles of apolipoprotein E4 in the pathogenesis of Alzheimer’s disease. Trends Mol Med. 2010;16(6):287–94. source

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    • cites [22] Mahley RW, Huang Y. Apolipoprotein E sets the stage: response to injury triggers neuropathology. Neuron. 2012;76(5):871–85. source

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  • Premisecitation

    Apolipoprotein E4 is the major genetic risk factor for late-onset familial and sporadic Alzheimer's disease.

    “Apolipoprotein (apo) E4, an isoform of the APOE gene in humans, is the major genetic risk factor for late-onset familial and sporadic AD [4–8], which account for most AD cases.”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [4] Huang Y, Mucke L. Alzheimer mechanisms and therapeutic strategies. Cell. 2012;148(6):1204–22. source

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    • cites [5] Kim J, Basak JM, Holtzman DM. The role of apolipoprotein E in Alzheimer’s disease. Neuron. 2009;63(3):287–303. source

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    • cites [6] Liu C-C, Kanekiyo T, Xu H, Bu G. Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy. Nat Rev Neurol. 2013;9(2):106–18. source

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    • cites [7] Kanekiyo T, Xu H, Bu G. ApoE and Aβ in Alzheimer’s disease: accidental encounters or partners? Neuron. 2014;81(4):740–54. source

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    • cites [8] Huang Y, Mahley RW. Apolipoprotein E: structure and function in lipid metabolism, neurobiology, and Alzheimer’s diseases. Neurobiol Dis. 2014;72:3–12. source

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  • Premisecitation

    ApoE plays major roles in Alzheimer's disease pathogenesis in both an amyloid-β-dependent and independent manner.

    “Overall, it has been demonstrated, both in vivo and in vitro, that apoE plays major roles in AD pathogenesis in both an Aβ-dependent and independent manner, and different cellular sources of apoE4 may contribute in distinct ways to AD pathogenesis [4–8, 12–14, 21, 22].”
    Quote in the paperSubstantial claim0 of 10 sources checked
    • cites [4] Huang Y, Mucke L. Alzheimer mechanisms and therapeutic strategies. Cell. 2012;148(6):1204–22. source

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    • cites [5] Kim J, Basak JM, Holtzman DM. The role of apolipoprotein E in Alzheimer’s disease. Neuron. 2009;63(3):287–303. source

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    • cites [6] Liu C-C, Kanekiyo T, Xu H, Bu G. Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy. Nat Rev Neurol. 2013;9(2):106–18. source

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    • cites [7] Kanekiyo T, Xu H, Bu G. ApoE and Aβ in Alzheimer’s disease: accidental encounters or partners? Neuron. 2014;81(4):740–54. source

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    • cites [8] Huang Y, Mahley RW. Apolipoprotein E: structure and function in lipid metabolism, neurobiology, and Alzheimer’s diseases. Neurobiol Dis. 2014;72:3–12. source

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    • cites [12] Bu G. Apolipoprotein E and its receptors in Alzheimer’s disease: pathways, pathogenesis and therapy. Nat Rev Neurosci. 2009;10(5):333–44. source

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    • cites [13] Mahley RW. Apolipoprotein E: from cardiovascular disease to neurodegenerative disorders. J Mol Med. 2016;94(7):739–46. source

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    • cites [14] Mahley RW, Weisgraber KH, Huang Y. Apolipoprotein E4: a causative factor and therapeutic target in neuropathology, including Alzheimer’s disease. Proc Natl Acad Sci U S A. 2006;103(15):5644–51. source

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    • cites [21] Huang Y. Aβ-independent roles of apolipoprotein E4 in the pathogenesis of Alzheimer’s disease. Trends Mol Med. 2010;16(6):287–94. source

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    • cites [22] Mahley RW, Huang Y. Apolipoprotein E sets the stage: response to injury triggers neuropathology. Neuron. 2012;76(5):871–85. source

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  • May combine two claims. 44
  • Classified as probably not a substantial claim. 6

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    Premisecitation

    ApoE4 is present in roughly 20-25% of the human population, and apoE4 carriers account for 60-75% of Alzheimer's disease cases in most clinical studies.

    “ApoE4 is present in roughly 20–25% of the human population, and apoE4 carriers account for 60–75% of AD cases in most clinical studies [11], highlighting the importance of apoE4 in AD pathogenesis.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [11] Farrer LA, Cupples LA, Haines JL, Hyman B, Kukull WA, Mayeux R, et al. Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease: a meta-analysis. JAMA J Am Med Assoc. 1997;278(16):1349–56. source

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    Premisecitation

    Both amyloid-β plaque and neurofibrillary tangle pathologies are exacerbated by the presence of apoE4.

    “Both of these pathologies are exacerbated by the presence of apoE4 [4–7, 12].”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [4] Huang Y, Mucke L. Alzheimer mechanisms and therapeutic strategies. Cell. 2012;148(6):1204–22. source

      Not checked in the free run.

    • cites [5] Kim J, Basak JM, Holtzman DM. The role of apolipoprotein E in Alzheimer’s disease. Neuron. 2009;63(3):287–303. source

      Not checked in the free run.

    • cites [6] Liu C-C, Kanekiyo T, Xu H, Bu G. Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy. Nat Rev Neurol. 2013;9(2):106–18. source

      Not checked in the free run.

    • cites [7] Kanekiyo T, Xu H, Bu G. ApoE and Aβ in Alzheimer’s disease: accidental encounters or partners? Neuron. 2014;81(4):740–54. source

      Not checked in the free run.

    • cites [12] Bu G. Apolipoprotein E and its receptors in Alzheimer’s disease: pathways, pathogenesis and therapy. Nat Rev Neurosci. 2009;10(5):333–44. source

      Not checked in the free run.

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    Premisecitation

    ApoE4 increases the risk and decreases the age of onset of Alzheimer's disease in a gene dose dependent manner.

    “ApoE4 increases the risk and decreases the age of onset of AD in a gene dose dependent manner [4–11].”
    Quote in the paperSubstantial claim0 of 8 sources checked
    • cites [4] Huang Y, Mucke L. Alzheimer mechanisms and therapeutic strategies. Cell. 2012;148(6):1204–22. source

      Not checked in the free run.

    • cites [5] Kim J, Basak JM, Holtzman DM. The role of apolipoprotein E in Alzheimer’s disease. Neuron. 2009;63(3):287–303. source

      Not checked in the free run.

    • cites [6] Liu C-C, Kanekiyo T, Xu H, Bu G. Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy. Nat Rev Neurol. 2013;9(2):106–18. source

      Not checked in the free run.

    • cites [7] Kanekiyo T, Xu H, Bu G. ApoE and Aβ in Alzheimer’s disease: accidental encounters or partners? Neuron. 2014;81(4):740–54. source

      Not checked in the free run.

    • cites [8] Huang Y, Mahley RW. Apolipoprotein E: structure and function in lipid metabolism, neurobiology, and Alzheimer’s diseases. Neurobiol Dis. 2014;72:3–12. source

      Not checked in the free run.

    • cites [9] Roses AD. Apolipoprotein E alleles as risk factors in Alzheimer’s disease. Annu Rev Med. 1996;47:387–400. source

      Not checked in the free run.

    • cites [10] Corder EH, Saunders AM, Strittmatter WJ, Schmechel DE, Gaskell PC, Small GW, et al. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science. 1993;261(5123):921–3. source

      Not checked in the free run.

    • cites [11] Farrer LA, Cupples LA, Haines JL, Hyman B, Kukull WA, Mayeux R, et al. Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease: a meta-analysis. JAMA J Am Med Assoc. 1997;278(16):1349–56. source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    The apoE3 and apoE4 amino acid sequences differ only at position 112, where apoE4 has an arginine instead of a cysteine.

    “The apoE3 and apoE4 amino acid sequences differ only at position 112 where apoE4 has an Arg instead of a Cys.”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [4] Huang Y, Mucke L. Alzheimer mechanisms and therapeutic strategies. Cell. 2012;148(6):1204–22. source

      Not checked in the free run.

    • cites [6] Liu C-C, Kanekiyo T, Xu H, Bu G. Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy. Nat Rev Neurol. 2013;9(2):106–18. source

      Not checked in the free run.

    • cites [8] Huang Y, Mahley RW. Apolipoprotein E: structure and function in lipid metabolism, neurobiology, and Alzheimer’s diseases. Neurobiol Dis. 2014;72:3–12. source

      Not checked in the free run.

    • cites [13] Mahley RW. Apolipoprotein E: from cardiovascular disease to neurodegenerative disorders. J Mol Med. 2016;94(7):739–46. source

      Not checked in the free run.

    • cites [14] Mahley RW, Weisgraber KH, Huang Y. Apolipoprotein E4: a causative factor and therapeutic target in neuropathology, including Alzheimer’s disease. Proc Natl Acad Sci U S A. 2006;103(15):5644–51. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In mutant human Tau-P301S transgenic mice, expression of apoE4 led to more advanced tau pathology, brain atrophy, and neuroinflammation.

    “In mutant human Tau-P301S transgenic mice, expression of apoE4 led to more advanced tau pathology, brain atrophy, and neuroinflammation.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [80] Shi Y, Yamada K, Liddelow SA, Smith ST, Zhao L, Luo W, et al. ApoE4 markedly exacerbates tau-mediated neurodegeneration in a mouse model of tauopathy. Nature. 2017;549(7673):523–7. source

      Not checked in the free run.

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    Premisecitation

    10-22% of Alzheimer's disease patients exhibit seizures, as do hAPPFAD mice, and the onset of these seizures precedes cognitive decline.

    “10–22% of AD patients exhibit seizures [98–100], as do hAPPFAD mice [101], and the onset of these seizures precedes cognitive decline [102].”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [98] Palop JJ, Mucke L. Epilepsy and cognitive impairments in Alzheimer disease. Arch Neurol. 2009;66(4):435–40. source

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    • cites [99] Palop JJ, Mucke L. Amyloid-β-induced neuronal dysfunction in Alzheimer’s disease: from synapses toward neural networks. Nat Neurosci. 2010;13(7):812–8. source

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    • cites [100] Vossel KA, Beagle AJ, Rabinovici GD, Shu H, Lee SE, Naasan G, et al. Seizures and epileptiform activity in the early stages of Alzheimer disease. JAMA Neurol. 2013;70(9):1158–66. source

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    Interpretationreasoning

    GABAergic dysfunction contributes to network-wide deficits in Alzheimer's disease, which may in turn harm cognition.

    “Thus, GABAergic dysfunction contributes to network-wide deficits in AD, which may in turn harm cognition.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    ApoE4 impairs adult hippocampal neurogenesis in mice and affects cortical thickness, brain activity, and mitochondrial function well before significant amyloid-β accumulation in human brains.

    “Furthermore, it impairs adult hippocampal neurogenesis in mice and affects cortical thickness, brain activity, and mitochondrial function well before significant Aβ accumulation in the human brains [74–76].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [74] Li G, Bien-Ly N, Andrews-Zwilling Y, Xu Q, Bernardo A, Ring K, et al. GABAergic interneuron dysfunction impairs hippocampal neurogenesis in adult apolipoprotein E4 Knockin mice. Cell Stem Cell. 2009;5(6):634–45. source

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    • cites [75] Shaw P, Lerch JP, Pruessner JC, Taylor KN, Rose AB, Greenstein D, et al. Cortical morphology in children and adolescents with different apolipoprotein E gene polymorphisms: an observational study. Lancet Neurol. 2007;6(6):494–500. source

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    Premisecitation

    ApoE4 impairs synaptogenesis and decreases dendritic spine density in vivo and in vitro in primary neuronal cultures.

    “ApoE4 impairs synaptogenesis and decreases dendritic spine density in vivo and in vitro in primary neuronal cultures [72, 73].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [72] Brodbeck J, McGuire J, Liu Z, Meyer-Franke A, Balestra ME, Jeong DE, et al. Structure-dependent impairment of intracellular apolipoprotein E4 trafficking and its detrimental effects are rescued by Small-molecule structure correctors. J Biol Chem. 2011;286(19):17217–26. source

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    Interpretationcitation

    These data support apoE4's gain of toxic effects on tau pathology and its related neurodegeneration and neuroinflammation, all independent of amyloid-β.

    “These data strongly support apoE4’s gain of toxic effects on tau pathology and its related neurodegeneration and neuroinflammation, all of which are independent of Aβ [80].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [80] Shi Y, Yamada K, Liddelow SA, Smith ST, Zhao L, Luo W, et al. ApoE4 markedly exacerbates tau-mediated neurodegeneration in a mouse model of tauopathy. Nature. 2017;549(7673):523–7. source

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    Premisecitation

    Levetiracetam reverses hyperexcitability and learning and memory deficits in an hAPPFAD mouse model of Alzheimer's disease and in aged mice.

    “Levetiracetam, an anti-epileptic drug, successfully reverses hyperexcitability and learning and memory deficits in an hAPPFAD mouse model of AD [103, 104] and in aged mice [105–107].”
    Quote in the paperNot a substantial claim0 of 5 sources checked
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    Premisecitation

    ApoE4 fragments escape the secretory pathway and enter the cytosol, where they stimulate tau phosphorylation and interact with mitochondria, leading to mitochondrial dysfunction and neurodegeneration.

    “These fragments escape the secretory pathway and enter the cytosol, where they stimulate tau-phosphorylation and interact with mitochondria, leading to mitochondrial dysfunction and neurodegeneration [4].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [4] Huang Y, Mucke L. Alzheimer mechanisms and therapeutic strategies. Cell. 2012;148(6):1204–22. source

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    Premisecitation

    Post-mortem tissue from Alzheimer's disease patients shows reduced GABA levels throughout the brain, particularly in temporal, parietal, and frontal cortices, and reduced GABA in cerebrospinal fluid.

    “Post-mortem tissue from AD patients shows reduced GABA level throughout the brain, particularly in temporal, parietal, and frontal cortices [84, 85].”
    Quote in the paperSubstantial claim0 of 6 sources checked
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    Premisecitation

    In apoE4 fragment transgenic mice, knocking out tau rescues GABAergic interneuron loss as well as learning and memory deficits, demonstrating the tau-dependent nature of apoE4-induced cognitive impairment.

    “In particular, GABAergic interneurons in the dentate gyrus (DG) are particularly vulnerable to apoE4 fragment-mediated neurotoxicity, and in apoE4 fragment transgenic mice, knocking out tau rescues GABAergic interneuron loss as well as learning and memory deficits, demonstrating the tau-dependent nature of apoE4-induced cognitive impairment [71].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [71] Andrews-Zwilling Y, Bien-Ly N, Xu Q, Li G, Bernardo A, Yoon SY, et al. Apolipoprotein E4 causes age- and tau-dependent impairment of GABAergic interneurons, leading to learning and memory deficits in mice. J Neurosci. 2010;30(41):13707–17. source

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    Interpretationcitation

    ApoE plays a significant role in the initiation of amyloid-β pathology; after amyloid-β pathology has been initiated, lowering apoE modulates plaque size and toxicity.

    “Taken together, these results indicate that apoE plays a significant role in the initiation of Aβ pathology; however, after Aβ pathology has been initiated, lowering apoE modulates plaque size and toxicity.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [54] Liu C-C, Zhao N, Fu Y, Wang N, Linares C, Tsai C-W, et al. ApoE4 accelerates early seeding of amyloid pathology. Neuron. 2017;96(5):1024–1032.e3. source

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    • cites [55] Huynh T-PV, Liao F, Francis CM, Robinson GO, Serrano JR, Jiang H, et al. Age-dependent effects of apoE reduction using antisense oligonucleotides in a model of β-amyloidosis. Neuron. 2017;96(5):1013–23. source

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    Premisecitation

    Knocking out apoE protected Tau-P301S mice from neurodegeneration and neuroinflammation.

    “Interestingly, knocking-out apoE (apoE-KO) protected the mice from Tau-P301S-induced neurodegeneration and neuroinflammation.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [80] Shi Y, Yamada K, Liddelow SA, Smith ST, Zhao L, Luo W, et al. ApoE4 markedly exacerbates tau-mediated neurodegeneration in a mouse model of tauopathy. Nature. 2017;549(7673):523–7. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Perineuronal nets are extracellular matrix structures which surround synapses of highly active neuronal subtypes and are associated with microglia.

    “Perineuronal nets are extracellular matrix structures which surround synapses of highly active neuronal subtypes and are associated with microglia [156].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [156] Brockner G, Brauer K, Hartg W, Wolff JR, Rickma MJ, Derouiche A, et al. Perineuronal nets provide a Polyanionic , glia-associated form of microenvironment around certain neurons in many parts of the rat brain. Glia. 1993;8(3):183–200. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Deletion of apoE4 in GABAergic interneurons, but not deletion of apoE4 in astrocytes, is sufficient to protect aged mice from apoE4-induced GABAergic interneuron loss and learning and memory deficits.

    “Importantly, deletion of apoE4 in GABAergic interneurons, but not deletion of apoE4 in astrocytes, is sufficient to protect aged mice from apoE4-induced GABAergic interneuron loss and learning and memory deficits [125].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [125] Knoferle J, Yoon SY, Walker D, Leung L, Gillespie AK, Tong LM, et al. Apolipoprotein E4 produced in GABAergic interneurons causes learning and memory deficits in mice. J Neurosci. 2014 Oct 15;34(42):14069–78. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Deletion of the Apoe gene suppresses microglial activation in response to amyloid-β accumulation and prevents migration of microglia toward amyloid plaques.

    “Deletion of the Apoe gene suppresses microglial activation in response to Aβ accumulation and prevents migration of microglia toward amyloid plaques [150].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [150] Frigerio CS, Wolfs L, Fattorelli N, Perry VH, Fiers M, De SB, et al. The Major risk factors for Alzheimer’s disease: age, sex, and genes modulate the microglia response to Aβ plaques. Cell Rep. 2019;27(4):1293–306. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The presence of apoE4 is correlated with smaller neuron size and increased DNA damage in temporal lobes of epilepsy patients.

    “The presence of apoE4 is correlated with smaller neuron size and increased DNA damage in temporal lobes of epilepsy patients [140]”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [140] Aboud O, Mrak RE, Boop F, Griffin ST. Apolipoprotein epsilon 3 alleles are associated with indicators of neuronal resilience. BMC Med. 2012;10:35. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In vivo electrophysiological recordings from aged apoE4-knock-in mice with odor memory deficits revealed increased local field potential response to odors in both the olfactory bulb and in primary olfactory cortex, which was attributed to inhibitory dysfunction.

    “In vivo electrophysiological recordings from aged apoE4-KI mice with odor memory deficits revealed increased local field potential response to odors in both the olfactory bulb and in primary olfactory cortex [148], which was attributed to inhibitory dysfunction.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [148] Peng KY, Mathews PM, Levy E, Wilson DA. Apolipoprotein E4 causes early olfactory network abnormalities and short-term olfactory memory impairments. Neuroscience. 2017;343:364–71. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The extent of apoE4-induced inhibitory interneuron loss correlates with both decreased adult hippocampal neurogenesis and with learning and memory deficits.

    “The extent of this inhibitory interneuron loss correlates with both decreased adult hippocampal neurogenesis and with learning and memory deficits [70, 74].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [70] Leung L, Andrews-Zwilling Y, Yoon SY, Jain S, Ring K, Dai J, et al. Apolipoprotein E4 causes age- and sex-dependent impairments of hilar GABAergic interneurons and learning and memory deficits in mice. PLoS One. 2012;7(12):e53569. source

      Not checked in the free run.

    • cites [74] Li G, Bien-Ly N, Andrews-Zwilling Y, Xu Q, Bernardo A, Ring K, et al. GABAergic interneuron dysfunction impairs hippocampal neurogenesis in adult apolipoprotein E4 Knockin mice. Cell Stem Cell. 2009;5(6):634–45. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Loss of tonic inhibition manifests itself most prominently in Alzheimer's disease patients as hypersynchrony, leading to epilepsy and olfactory processing deficits, as well as hyperactivity, leading to aberrantly increased activation of cortical and hippocampal networks.

    “Loss of tonic inhibition manifests itself most prominently in AD patients as hypersynchrony, leading to epilepsy and olfactory processing deficits, as well as hyperactivity, leading to aberrantly increased activation of cortical and hippocampal networks [130].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [130] Lee V, Maguire J. The impact of tonic GABAA receptor-mediated inhibition on neuronal excitability varies across brain region and cell type. Front Neural Circuits. 2014;8:3. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Converting APOE4 to APOE3 by gene editing rescued tau hyperphosphorylation, amyloid-β40 and amyloid-β42 overproduction, and GABAergic interneuron loss, suggesting that neuronal apoE4 expression alone was sufficient to induce these interneuron pathologies.

    “Converting APOE4 to APOE3 by gene editing rescued these pathologies, including tau hyperphosphorylation, Aβ40 and Aβ42 overproduction, and GABAergic interneuron loss, suggesting that neuronal apoE4 expression alone was sufficient to induce these interneuron pathologies.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [128] Wang C, Najm R, Xu Q, Jeong D, Walker D, Balestra ME, et al. Gain of toxic apolipoprotein E4 effects in human iPSC-derived neurons is ameliorated by a Small-molecule structure corrector. Nat Med. 2018;24(5):647–57. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    There was no significant loss of glutamatergic neurons and dopaminergic neurons in apoE4/4 hiPSC-derived neuron cultures, suggesting a preferential detrimental effect of apoE4 on GABAergic neurons.

    “Importantly, there was no significant loss of glutamatergic neurons and dopaminergic neurons in apoE4/4 hiPSC-derived neuron cultures, suggesting a preferential detrimental effect of apoE4 on GABAergic neurons.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [128] Wang C, Najm R, Xu Q, Jeong D, Walker D, Balestra ME, et al. Gain of toxic apolipoprotein E4 effects in human iPSC-derived neurons is ameliorated by a Small-molecule structure corrector. Nat Med. 2018;24(5):647–57. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    ApoE4 produced within GABAergic interneurons is detrimental to their survival in vivo, leading to deficits in both learning and memory in Alzheimer's disease models.

    “These findings suggest that, although the majority of apoE is produced in astrocytes, it is apoE4 produced within GABAergic interneurons that is detrimental to their survival in vivo which leads to deficits in both learning and memory in AD models.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    ApoE4 carriers show particularly marked deficits in odor identification and memory relative to non-carriers.

    “ApoE4 carriers show particularly marked deficits in odor identification and memory relative to non-carriers [146]”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [146] Misiak MM, Hipolito MS, Ressom HW, Obisesan TO, Manaye KF, Nwulia EA. Apo E4 alleles and impaired olfaction as predictors of Alzheimer’s disease. Clin Exp Psychol. 2017;3(4):169. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Bolstering inhibitory function, either through systemic GABA-agonist treatment or through transplant of mouse derived inhibitory interneuron progenitors directly into the hippocampus, restores learning and memory in aged apoE4-knock-in mice without or with mutant hAPPFAD expression.

    “Strikingly, bolstering inhibitory function, either through systemic GABA-agonist treatment [126] or through transplant of mouse derived inhibitory interneuron progenitors directly into the hippocampus [127], restores learning and memory in aged apoE4-KI mice without or with mutant hAPPFAD expression.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [126] Tong LM, Yoon SY, Andrews-Zwilling Y, Yang A, Lin V, Lei H, et al. Enhancing GABA signaling during middle adulthood prevents age-dependent GABAergic interneuron decline and learning and memory deficits in ApoE4 mice. J Neurosci. 2016;36(7):2316–22. source

      Not checked in the free run.

    • cites [127] Tong LM, Djukic B, Arnold C, Gillespie AK, Yoon SY, Wang MM, et al. Inhibitory interneuron progenitor transplantation restores Normal learning and memory in ApoE4 Knock-in mice without or with Aβ accumulation. J Neurosci. 2014;34(29):9506–15. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    ApoE4 carriers have a higher risk and earlier onset of developing idiopathic or secondary temporal lobe epilepsy.

    “ApoE4 carriers have a higher risk [132–136] and earlier onset [137–139] of developing idiopathic or secondary temporal lobe epilepsy.”
    Quote in the paperSubstantial claim0 of 8 sources checked
    • cites [132] Fu Y, Lv R, Jin L, Lu Q, Shao X, He J, et al. Association of apolipoprotein E polymorphisms with temporal lobe epilepsy in a Chinese Han population. Epilepsy Res. 2010;91(2–3):253–9. source

      Not checked in the free run.

    • cites [133] Li Z, Ding C, Gong X, Wang X, Cui T. Apolipoprotein E ε4 allele was associated with Nonlesional mesial temporal lobe epilepsy in Han Chinese population. Medicine (Baltimore). 2016;95(9):e2894. source

      Not checked in the free run.

    • cites [134] Diaz-Arrastia R, Gong Y, Fair S, Scott KD, Garcia MC, Carlile MC, et al. Increased risk of late posttraumatic seizures associated with inheritance of APOE ∈4 allele. Arch Neurol. 2003;60(6):818–22. source

      Not checked in the free run.

    • cites [135] Salzmann A, Perroud N, Crespel A, Lambercy C, Malafosse A. Candidate genes for temporal lobe epilepsy: a replication study. Neurol Sci. 2008;29(6):397–403. source

      Not checked in the free run.

    • cites [136] Johnson EL, Krauss GL, Lee AK, Schneider ALC, Dearborn JL, Kucharska-Newton AM, et al. Association between midlife risk factors and late-onset epilepsy: results from the atherosclerosis risk in communities study. JAMA Neurol. 2018;75(11):1375–82. source

      Not checked in the free run.

    • cites [137] Briellmann RS, Torn-Broers Y, Busuttil BE, Major BJ, Kalnins RM, Olsen M, et al. APOE ε4 genotype is associated with an earlier onset of chronic temporal lobe epilepsy. Neurology. 2000;55(3):435–7. source

      Not checked in the free run.

    • cites [138] Kauffman MA, Consalvo D, Moron DG, Lereis VP, Kochen S. ApoE ɛ4 genotype and the age at onset of temporal lobe epilepsy: a case–control study and meta-analysis. Epilepsy Res. 2010;90(3):234–9. source

      Not checked in the free run.

    • cites [139] Leal B, Chaves J, Carvalho C, Bettencourt A, Freitas J, Lopes J, et al. Age of onset of mesial temporal lobe epilepsy with hippocampal sclerosis: the effect of apolipoprotein E and febrile seizures. Int J Neurosci. 2017;127(9):800–4. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Both activated microglia displacing inhibitory synapses and increased CX3CR1 suppressing GABAA receptor signaling could contribute to GABAergic inhibitory network deficits in the context of apoE4.

    “both of which could contribute to GABAergic inhibitory network deficits in the context of apoE4.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    ApoE4/4 GABAergic interneurons showed degeneration and displayed significantly elevated phosphorylated tau levels compared to apoE3/3 GABAergic interneurons.

    “ApoE4/4 GABAergic interneurons in particular showed degeneration and displayed significantly elevated phosphorylated tau levels compared to apoE3/3 GABAergic interneurons.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [128] Wang C, Najm R, Xu Q, Jeong D, Walker D, Balestra ME, et al. Gain of toxic apolipoprotein E4 effects in human iPSC-derived neurons is ameliorated by a Small-molecule structure corrector. Nat Med. 2018;24(5):647–57. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    ApoE4 undergoes proteolytic cleavage generating neurotoxic fragments only when produced in neurons, but not when produced in astrocytes.

    “ApoE4 undergoes proteolytic cleavage which generates neurotoxic fragments only when produced in neurons, but not when produced in astrocytes [20].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [20] Brecht WJ, Harris FM, Chang S, Tesseur I, Yu G-Q, Xu Q, et al. Neuron-specific apolipoprotein E4 proteolysis is associated with increased tau phosphorylation in brains of transgenic mice. J Neurosci. 2004;24(10):2527–34. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The adverse effects of apoE4 are prevented by tau removal, indicating a direct link between tau pathology, apoE4, and GABAergic interneuron death.

    “The adverse effects of apoE4 are prevented by tau removal, indicating a direct link between tau pathology, apoE4, and GABAergic interneuron death [71].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [71] Andrews-Zwilling Y, Bien-Ly N, Xu Q, Li G, Bernardo A, Yoon SY, et al. Apolipoprotein E4 causes age- and tau-dependent impairment of GABAergic interneurons, leading to learning and memory deficits in mice. J Neurosci. 2010;30(41):13707–17. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    Injury or aging-related stress induces neuronal apoE expression.

    “We present a model wherein injury or aging-related stress induces neuronal apoE expression.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Premisenone given

    Due to its pathological conformation (domain interaction), apoE4 is more susceptible to proteolytic cleavage than apoE3.

    “Due to its pathological conformation (domain interaction), apoE4 is more susceptible to proteolytic cleavage than apoE3”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    ApoE4 leads to reduced instances as well as accuracy of spatial memory consolidation.

    “Thus, apoE4 leads to reduced instances as well as accuracy of spatial memory consolidation.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Levetiracetam treatment of amnestic MCI patients reduces hippocampal over-activation and improves cognitive performance during a recognition memory task.

    “as levetiracetam treatment of amnestic MCI patients both reduces hippocampal over-activation and improves cognitive performance during a recognition memory task [109, 175].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [109] Bakker A, Krauss GL, Albert MS, Speck CL, Jones LR, Stark CE, et al. Reduction of hippocampal hyperactivity improves cognition in amnestic mild cognitive impairment. Neuron. 2012;74(3):467–74. source

      Not checked in the free run.

    • cites [175] Bakker A, Albert MS, Krauss G, Speck CL, Gallagher M. Response of the medial temporal lobe network in amnestic mild cognitive impairment to therapeutic intervention assessed by fMRI and memory task performance. NeuroImage Clin. 2015;7:688–98. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    GABAA receptor potentiators or agonists ameliorate apoE4- or amyloid-induced toxicity and improve cognition in rodent models of AD and normal aging.

    “GABAA receptor potentiators or agonists ameliorate apoE4- or amyloid-induced toxicity and improve cognition in rodent models of AD and normal aging [126, 194].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [126] Tong LM, Yoon SY, Andrews-Zwilling Y, Yang A, Lin V, Lei H, et al. Enhancing GABA signaling during middle adulthood prevents age-dependent GABAergic interneuron decline and learning and memory deficits in ApoE4 mice. J Neurosci. 2016;36(7):2316–22. source

      Not checked in the free run.

    • cites [194] Li Y, Sun H, Chen Z, Xu H, Bu G, Zheng H. Implications of GABAergic neurotransmission in Alzheimer’s disease. Front Aging Neurosci. 2016;8:31.

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Network hyperactivity is an overarching symptom of Alzheimer's disease and is evident in human apoE4 carriers.

    “Network hyperactivity is an overarching symptom of AD and is evident in human apoE4 carriers.”
    Quote in the paperSubstantial claim0 of 8 sources checked
    • cites [162] Persson J, Lind J, Larsson A, Ingvar M, Sleegers K, Van Broeckhoven C, et al. Altered deactivation in individuals with genetic risk for Alzheimer’s disease. Neuropsychologia. 2008;46(6):1679–87. source

      Not checked in the free run.

    • cites [163] Fleisher AS, Sherzai A, Taylor C, Langbaum JBS, Chen K, Buxton RB. Resting-state BOLD networks versus task-associated functional MRI for distinguishing Alzheimer’s disease risk groups. Neuroimage. 2009;47(4):1678–90. source

      Not checked in the free run.

    • cites [164] Pihlajamäki M, Sperling RA. Functional MRI assessment of task-induced deactivation of the default mode network in Alzheimer’s disease and at-risk older individuals. Behav Neurol. 2009;21(1):77–91. source

      Not checked in the free run.

    • cites [172] Dickerson BC, Salat DH, Greve DN, Chua EF, Rand-Giovannetti E, Rentz DM, et al. Increased hippocampal activation in mild cognitive impairment compared to normal aging and AD. Neurology. 2005;65(3):404–11. source

      Not checked in the free run.

    • cites [173] Bondi MW, Houston WS, Eyler LT, Brown GG. fMRI evidence of compensatory mechanisms in older adults at genetic risk for Alzheimer disease. Neurology. 2005;64(3):501–8. source

      Not checked in the free run.

    • cites [179] Filippini N, MacIntosh BJ, Hough MG, Goodwin GM, Frisoni GB, Smith SM, et al. Distinct patterns of brain activity in young carriers of the APOE-ε4 allele. Proc Natl Acad Sci U S A. 2009;106(17):7209–14. source

      Not checked in the free run.

    • cites [180] Bookheimer SY, Strojwas MH, Cohen MS, Saunders AM, Pericak-Vance MA, Mazziotta JC, et al. Patterns of brain activation in people at risk for Alzheimer’s disease. N Engl J Med. 2000;343(7):450–6. source

      Not checked in the free run.

    • cites [181] Dennis NA, Browndyke JN, Stokes J, Need A, Burke JR, Welsh-Bohmer KA, et al. Temporal lobe functional activity and connectivity in young adult APOE ɛ4 carriers. Alzheimers Dement. 2010;6(4):303–11. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Network dysfunction and hyperexcitability induce further stress, and therefore more neuronal expression of apoE.

    “as well as induce further stress, and therefore more neuronal expression of apoE.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    GABAergic interneurons are selectively vulnerable to intracellularly produced apoE4, through a tau dependent mechanism, which leads to their dysfunction and eventual death.

    “GABAergic interneurons are selectively vulnerable to intracellularly produced apoE4, through a tau dependent mechanism, which leads to their dysfunction and eventual death.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In mice, slow gamma frequency visual or audio input entrains neural firing to this frequency in the cortex and hippocampus and reduces Aβ pathology and microglial abnormalities.

    “In mice, slow gamma frequency visual or audio input entrains neural firing to this frequency in the cortex and hippocampus and reduces Aβ pathology and microglial abnormalities [204, 205].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [204] Iaccarino HF, Singer AC, Martorell AJ, Rudenko A, Gao F, Gillingham TZ, et al. Gamma frequency entrainment attenuates amyloid load and modifies microglia. Nature. 2016;540(7632):230–5. source

      Not checked in the free run.

    • cites [205] Martorell AJ, Paulson AL, Suk H, Boyden ES, Singer AC, Tsai L. Multi-sensory gamma stimulation ameliorates Alzheimer’s-associated pathology and improves cognition. Cell. 2019;177(2):256–71 e22. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Transplanting Nav1.1-overexpressing interneurons derived from mouse MGE into an hAPPFAD mouse model enhances behavior-dependent gamma oscillatory activity, reduces network hypersynchrony, and improves cognitive function.

    “transplanting Nav1.1-overexpressing interneurons derived from the mouse MGE into an hAPPFAD mouse model enhances behavior-dependent gamma oscillatory activity, reduces network hypersynchrony, and improves cognitive function [213].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [213] Martinez-Losa M, Tracy TE, Ma K, Verret L, Clemente-Perez A, Khan AS, et al. Nav1.1-overexpressing interneuron transplants restore brain rhythms and cognition in a mouse model of Alzheimer’s disease. Neuron. 2018;98(1):75–89.e5. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Optogenetically driving inhibitory interneurons specifically enhances slow gamma frequency oscillations throughout cortex, reducing circuit noise while amplifying circuit signal.

    “Two foundational optogenetic studies demonstrated that optogenetically driving inhibitory interneurons specifically enhances slow gamma frequency oscillations throughout cortex, reducing circuit noise while amplifying circuit signal [201, 202].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [201] Cardin JA, Carlén M, Meletis K, Knoblich U, Zhang F, Deisseroth K, et al. Driving fast-spiking cells induces gamma rhythm and controls sensory responses. Nature. 2009;459(7247):663–7. source

      Not checked in the free run.

    • cites [202] Sohal VS, Zhang F, Yizhar O, Deisseroth K. Parvalbumin neurons and gamma rhythms enhance cortical circuit performance. Nature. 2009;459(7247):698–702. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In humans, transcranial magnetic stimulation enhances cortical slow waves and thus improves task performance.

    “In humans, transcranial magnetic stimulation enhances cortical slow waves and thus improve task performance [203].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [203] Ketz N, Jones AP, Bryant NB, Clark VP, Pilly PK. Closed-loop slow-wave tACS improves sleep-dependent long-term memory generalization by modulating endogenous oscillations. J Neurosci. 2018;38(33):7314–26. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Levetiracetam improved cognition and reduced hippocampal hyperactivity in preclinical and initial clinical studies.

    “with the exception of levetiracetam that improved cognition and reduced hippocampal hyperactivity in preclinical and initial clinical studies [107–110, 175, 197–199].”
    Quote in the paperSubstantial claim0 of 8 sources checked
    • cites [107] Haberman RP, Branch A, Gallagher M. Targeting neural hyperactivity as a treatment to stem progression of late-onset Alzheimer’s disease. Neurotherapeutics. 2017;14(3):662–76. source

      Not checked in the free run.

    • cites [108] Schoenberg MR, Rum RS, Osborn KE, Werz MA. A randomized, double-blind, placebo-controlled crossover study of the effects of levetiracetam on cognition, mood, and balance in healthy older adults. Epilepsia. 2017;58(9):1566–74. source

      Not checked in the free run.

    • cites [109] Bakker A, Krauss GL, Albert MS, Speck CL, Jones LR, Stark CE, et al. Reduction of hippocampal hyperactivity improves cognition in amnestic mild cognitive impairment. Neuron. 2012;74(3):467–74. source

      Not checked in the free run.

    • cites [110] Cumbo E, Ligori LD. Levetiracetam, lamotrigine, and phenobarbital in patients with epileptic seizures and Alzheimer’s disease. Epilepsy Behav. 2010;17(4):461–6. source

      Not checked in the free run.

    • cites [175] Bakker A, Albert MS, Krauss G, Speck CL, Gallagher M. Response of the medial temporal lobe network in amnestic mild cognitive impairment to therapeutic intervention assessed by fMRI and memory task performance. NeuroImage Clin. 2015;7:688–98. source

      Not checked in the free run.

    • cites [197] Helmstaedter C, Witt J-A. Cognitive outcome of antiepileptic treatment with levetiracetam versus carbamazepine monotherapy: a non-interventional surveillance trial. Epilepsy Behav. 2010;18(1–2):74–80. source

      Not checked in the free run.

    • cites [198] Lippa CF, Rosso A, Hepler M, Jenssen S, Pillai J, Irwin D. Levetiracetam: a practical option for seizure management in elderly patients with cognitive impairment. Am J Alzheimer’s Dis Other Dementiasr. 2010;25(2):149–54. source

      Not checked in the free run.

    • cites [199] Haberman RP, Koh MT, Gallagher M. Heightened cortical excitability in aged rodents with memory impairment. Neurobiol Aging. 2017;54:144–51. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    GABAergic interneuron progenitor transplantation has potential to be an effective method to correct seizure activity in an epilepsy model.

    “it has been shown that GABAergic interneuron progenitor transplantation has potential to be an effective method to correct seizure activity in an epilepsy model [212].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [212] Cunningham M, Cho J-H, Leung A, Savvidis G, Ahn S, Moon M, et al. hPSC-derived maturing GABAergic interneurons ameliorate seizures and abnormal behavior in epileptic mice. Cell Stem Cell. 2014;15(5):559–73. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Exogenous neuregulin 1 has been used to restore hippocampal theta synchrony and fear conditioning in a mouse model of schizophrenia.

    “and has been used to restore hippocampal theta synchrony and fear conditioning in a mouse model of schizophrenia, which showed inhibitory impairments [207].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [207] Marissal T, Salazar RF, Bertollini C, Mutel S, De Roo M, Rodriguez I, et al. Restoring wild-type-like CA1 network dynamics and behavior during adulthood in a mouse model of schizophrenia. Nat Neurosci. 2018;21(10):1412–20. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Anti-epileptic agents show promise in animal models but have not produced cognitive improvements in clinical trials, with the exception of levetiracetam.

    “Anti-epileptic agents similarly show promise in animal models [103, 104], but have not produced cognitive improvements in clinical trials [85], with the exception of levetiracetam that improved cognition and reduced hippocampal hyperactivity in preclinical and initial clinical studies [107–110, 175, 197–199].”
    Quote in the paperSubstantial claim0 of 10 sources checked
    • cites [103] Sanchez PE, Zhu L, Verret L, Vossel KA, Orr AG, Cirrito JR, et al. Levetiracetam suppresses neuronal network dysfunction and reverses synaptic and cognitive deficits in an Alzheimer’s disease model. Proc Natl Acad Sci. 2012;109(42):E2895–903. source

      Not checked in the free run.

    • cites [104] Shi J-Q, Wang B-R, Tian Y-Y, Xu J, Gao L, Zhao S-L, et al. Antiepileptics Topiramate and Levetiracetam alleviate behavioral deficits and reduce neuropathology in APPswe/PS1dE9 transgenic mice. CNS Neurosci Ther. 2013;19(11):871–81. source

      Not checked in the free run.

    • cites [85] Lanctôt KL, Herrmann N, Mazzotta P, Khan LR, Ingber N. GABAergic function in Alzheimer’s disease: evidence for dysfunction and potential as a therapeutic target for the treatment of Behavioural and psychological symptoms of dementia. Can J Psychiatr. 2016;49(7):439–53. source

      Not checked in the free run.

    • cites [107] Haberman RP, Branch A, Gallagher M. Targeting neural hyperactivity as a treatment to stem progression of late-onset Alzheimer’s disease. Neurotherapeutics. 2017;14(3):662–76. source

      Not checked in the free run.

    • cites [108] Schoenberg MR, Rum RS, Osborn KE, Werz MA. A randomized, double-blind, placebo-controlled crossover study of the effects of levetiracetam on cognition, mood, and balance in healthy older adults. Epilepsia. 2017;58(9):1566–74. source

      Not checked in the free run.

    • cites [109] Bakker A, Krauss GL, Albert MS, Speck CL, Jones LR, Stark CE, et al. Reduction of hippocampal hyperactivity improves cognition in amnestic mild cognitive impairment. Neuron. 2012;74(3):467–74. source

      Not checked in the free run.

    • cites [110] Cumbo E, Ligori LD. Levetiracetam, lamotrigine, and phenobarbital in patients with epileptic seizures and Alzheimer’s disease. Epilepsy Behav. 2010;17(4):461–6. source

      Not checked in the free run.

    • cites [175] Bakker A, Albert MS, Krauss G, Speck CL, Gallagher M. Response of the medial temporal lobe network in amnestic mild cognitive impairment to therapeutic intervention assessed by fMRI and memory task performance. NeuroImage Clin. 2015;7:688–98. source

      Not checked in the free run.

    • cites [197] Helmstaedter C, Witt J-A. Cognitive outcome of antiepileptic treatment with levetiracetam versus carbamazepine monotherapy: a non-interventional surveillance trial. Epilepsy Behav. 2010;18(1–2):74–80. source

      Not checked in the free run.

    • cites [198] Lippa CF, Rosso A, Hepler M, Jenssen S, Pillai J, Irwin D. Levetiracetam: a practical option for seizure management in elderly patients with cognitive impairment. Am J Alzheimer’s Dis Other Dementiasr. 2010;25(2):149–54. source

      Not checked in the free run.

49 of 49

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Previous studies have reported LTP deficits in APOE4-carrying mice compared to APOE3-carrying mice, in addition to morphological alterations in CA1 hippocampal neurons such as shortened dendritic length, reduced spine density, decreased levels of the presynaptic glutamatergic transporter vGLUT and GABAergic interneuron loss.

    “Previous studies have reported LTP deficits in APOE4-carrying mice compared to APOE3-carrying mice, in addition to morphological alterations in CA1 hippocampal neurons such as shortened dendritic length, reduced spine density, decreased levels of the presynaptic glutamatergic transporter vGLUT and GABAergic interneuron loss [79–81].”

    From Analysis of early effects of human APOE isoforms on Alzheimer’s disease and type III hyperlipoproteinemia pathways using knock-in rat models with humanized APP and APOE (2024) · cites this paper as [81]

    Split into 2 atoms — 0 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 1 unverifiable. Expand the claim to see per-atom verdicts.

    Experimental — accuracy not yet measured

  • APOE4 is associated with age-dependent decreases in GABA release, postsynaptic GABAergic response, and the density of hilar GABAergic interneurons in the hippocampus, all of which impairs inhibitory transmission.

    “APOE4 is associated with age-dependent decreases in GABA release, postsynaptic GABAergic response, and the density of hilar GABAergic interneurons in the hippocampus, all of which impairs inhibitory transmission (Najm et al., 2019).”

    From APOE4 reduces hippocampal expression of phosphoglycerate kinase 1 and sodium potassium pump to enhance seizure susceptibility in mice (2026) · cites this paper as Najm et al., 2019

    The Background section on GABAergic interneuron susceptibility reports an age- and tau-dependent decrease in hilar GABAergic interneurons in apoE4 knock-in mice. The section on inhibitory network dysfunction links interneuron loss to reduced inhibitory function. The cited paper does not report age-dependent decreases in GABA release or postsynaptic GABAergic response, so those parts of the claim are unsupported. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

  • ApoE4 may have direct pathologic effects on neurons and neuronal networks independent of effects on amyloid and tau pathology.

    “ApoE4 may have direct pathologic effects on neurons and neuronal networks independent of effects on amyloid and tau pathology”

    From Alzheimer Disease: An Update on Pathobiology and Treatment Strategies (2019) · cites this paper as Najm et al., 2019

  • GABAergic inhibitory networks are impaired in AD and may contribute to cognitive impairment; ApoE4-TR mice have decreased numbers of GABAergic interneurons in the hippocampus correlating with learning deficits.

    “GABAergic inhibitory networks are impaired in AD and may contribute to cognitive impairment”

    From Alzheimer Disease: An Update on Pathobiology and Treatment Strategies (2019) · cites this paper as Najm et al., 2019

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Magnetic stimulation claim cites an electrical-stimulation study

    Minor

    The text describes the cited human study as using transcranial magnetic stimulation, but reference 203 identifies the intervention as tACS (transcranial alternating current stimulation).

1 of 1

Cites

Flagged first, then by citations

Research works printed but not linked: 1

  1. Frieden C, Garai K. Structural differences between apoE3 and apoE4 may be useful in developing therapeutic agents for Alzheimer’s disease. Proc Natl Acad Sci. 2012;109(28):E1972–9. · DOI

Cited by

Sorted by citations

Authors
Najm, R., Jones, E. A., & Huang, Y.
Affiliations
Gladstone Institutes (US)
Corresponding author
Huang, Yadong
ORCID
Venue
Molecular Neurodegeneration
Publisher
Springer Science and Business Media LLC
Published
2019-06-11
Volume
14
Issue
1
Pages
24-24
ISSN
1750-1326 (ISSN-L)
DOI
10.1186/s13024-019-0324-6
PMC
PMC6558779
OpenAlex
W2953148923
Semantic Scholar
d4943dea227d4e02e59fea2b3183493cd5990395
Cited by
183
References
212
Citations by year
2026: 18 · 2025: 31 · 2024: 22 · 2023: 22 · 2022: 23 · 2021: 38 · 2020: 22 · 2019: 6 · 2018: 1
FWCI
2.61
Type
journal article
Language
en
Open access
Licence
Locations
  • Molecular Neurodegeneration (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • eScholarship (California Digital Library) (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • eScholarship (California Digital Library) (submittedVersion)
Funders
National Institute on Aging (AG048030, AG048017, AG047655, AG055421, AG055682, 1F31AG057150)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Keywords
APOE ε4, Alzheimer's disease, GABAergic interneurons, hippocampus, cognitive decline, hyperexcitability, induced pluripotent stem cell models, learning and memory impairment
MeSH terms
Alzheimer Disease, Animals, Humans, Memory, Memory Disorders, Nerve Net, Apolipoprotein E4, Induced Pluripotent Stem Cells

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-06.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-06.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

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